Alzheimer's disease (AD) is the only cause of death among the top ten that cannot be prevented, cured, or even slowed, making it urgent to identify novel therapeutic targets for treatment of AD. It is generally accepted that toxic amyloid ? (A?) peptides are the key pathogenic factor for AD. However, AD progression and clinical presentation are highly heterogeneous and determined by multiple genetic and environmental factors. Therefore, in order to develop effective disease-modifying therapies, it is necessary to fully understand the action of A? and identify underlying mechanisms that modulate its effects on cognitive functions. Our unpublished data revealed that A?42 oligomers (the major toxic species of A? peptides) act as allosteric modulators with nanomolar affinity for the ?2A-adrenergic receptor (?2AAR). This is the first example in which A? functions as an allosteric modulator of a G protein-coupled receptor (GPCR) with nanomolar affinity. We found that A?42 binding to ?2AAR resulted in aberrant coupling of ?2AAR to activation of a new signaling effector that promotes neuronal dysfunction and cognitive impairment. The A?-dependent pathological coupling of ?2AAR signaling provides a novel mechanism underlying A?-induced toxicity to brain function, and suggests that the A?-?2AAR interaction represents a potential disease-specific target for AD treatment. The primary objective of this proposal is to address the cellular and molecular mechanisms and in vivo relevance of the A?-?2AAR interaction in exacerbating AD-related neuronal dysfunction and cognitive impairment using combined cellular, molecular and genetic approaches. We will first determine the cellular aspect of detrimental effects induced by the A?-?2AAR interaction in neurons. Second, we will identify the molecular mechanism critical for A?-dependent pathological coupling of ?2AAR signaling and determine the role of G proteins and ?arrestins in this process. Third, we will determine the in vivo functional relevance of the A?-?2AAR interaction in exacerbating AD-related cognitive deficits. Successfully accomplishing this study will significantly advance our understanding of the molecular and cellular mechanisms underlying A? actions in disrupting cognitive function in AD. Targeting the disease-specific interaction between A? oligomers and ?2AAR represents a potential safe and effective approach to improve cognitive function in AD.